WO98/52948 details inhibitors of ceramide-mediated signal transduction. One of the types of inhibitors described is of the following formula: wherein Y1 can be N—R6, R6 can be unsubstituted aryl-alkyl or unsubstituted heterocyclic-alkyl and R1 can be a substituted aryl group. WO98/52948 does not mention factor Xa inhibition or show compounds like those of the present invention.
WO99/39131 describes heterobicyclic Factor Xa inhibitors of which the following is an example formula: wherein Z is C or N, G is a mono- or bicyclic group, A is a cyclic moiety and B is a basic group or a cyclic moiety. Compounds with this substitution pattern are not considered to be part of the present invention.
WO00/40583 and WO00/20416 describes factor Xa inhibitors of the following formula: wherein R is alkyl or cycloalkyl, R1 and R2 are optionally substituted phenyl, naphthyl, or biphenyl.
WO01/19798 describes factor Xa inhibitors of the following formula:A—Q—D—E—G—J—Xwherein A, D, G, and X can be phenyl or heterocycle. However, none of the presently claimed compounds are exemplified or suggested in WO01/19798.
None of the above references teaches or suggests the compounds of the present invention that are described in detail below.
Activated factor Xa, whose major practical role is the generation of thrombin by the limited proteolysis of prothrombin, holds a central position that links the intrinsic and extrinsic activation mechanisms in the final common pathway of blood coagulation. The generation of thrombin, the final serine protease in the pathway to generate a fibrin clot, from its precursor is amplified by formation of prothrombinase complex (factor Xa, factor V, Ca2+ and phospholipid). Since it is calculated that one molecule of factor Xa can generate 138 molecules of thrombin (Elodi, S, Varadi, K.: Optimization of conditions for the catalytic effect of the factor IXa-factor VIII Complex: Probable role of the complex in the amplification of blood coagulation. Thromb. Res. 1979, 15, 617-629), inhibition of factor Xa may be more efficient than inactivation of thrombin in interrupting the blood coagulation system.
Therefore, efficacious and specific inhibitors of factor Xa are needed as potentially valuable therapeutic agents for the treatment of thromboembolic disorders. It is thus desirable to discover new factor Xa inhibitors.